Clinical and pharmacological evaluation of different preparations of oral erythromycin.

The activity of erythromycin stearate in respiratory tract infections was evaluated. This study involved 269 out-patients. Of these, 76 satisfied the strict criteria for detailed bacteriological study with positive cultures of a known pathogen before treatment and bacteriological follow-up after treatment. The results of erythromycin stearate were good against the haemolytic streptococcal infections. The activity of this antibiotic was shown to be insufficient against Haemophilus influenzae. A second clinical trial with 20 patients with acute exacerbations of chronic bronchitis demonstrated quite good activity from erythromycin ethylsuccinate and no intolerance when administered in a dose of 1 g q.i.d. The administration of 1 g of the ethylsuccinate immediately after a meal gave a peak serum concentration after 60 min of 3.36 micrograms/ml. Blood levels on the fourth day of this treatment showed some accumulation, concentrations of greater than 4 micrograms/ml being found at 30, 60 and 90 min after the dose. With its good absorption, its lack of toxicity and its reputation for good diffusion into bronchial secretions, we consider that erythromycin ethylsuccinate should have a major place in the treatment of respiratory tract infections.     

Doppler evaluation of the effects of pharmacological treatment of portal hypertension.

The splanchnic pharmacodynamic effects of the drugs used for the treatment of hemorrhagic complications of portal hypertension were poorly clarified until some years ago. The introduction of Doppler ultrasound provided a powerful tool to investigate such hemodynamic effects and brought new insights in this field. The present article reviews the pharmacodynamics of the substances used in the treatment of portal hypertension, with particular regard to the effects assessable by duplex Doppler ultrasonography.     

Hemodynamic and pharmacological evaluation of the vasodilator and vasoconstrictor effects of endothelin-1 in rats

In awake normotensive and spontaneously hypertensive rats as well as pentobarbital-anesthetized normotensive rats, endothelin-1 (ET-1, 0.063-0.5 nmol/kg i.v.) produced rapidly appearing, transient, dose-related falls in mean carotid artery blood pressure followed by slowly developing small pressor responses. In the latter preparation, the hypotension was due to a decrease in systemic vascular resistance inasmuch as cardiac output increased slightly. Bilateral vagotomy, BW 755c, glibenclamide, idazoxan, propranolol, methylatropine, methysergide or promethazine pretreatment failed to modify the hypotension induced by ET-1 (0.25 nmol/kg i.v.), but this effect was blocked entirely when ET-1 was injected 8 min after starting an i.v. infusion of ET-1 (0.1 nmol/kg/min for 10 min). In pithed rats, ET-1 (0.125-1.0 nmol/kg i.v.) produced sustained pressor responses which were accompanied by reductions in cardiac output. This peptide (0.25 nmol/kg i.v.) did not affect renal vascular resistance significantly but increased (200%) mesenteric resistance substantially more (3-fold) than systemic or hindquarter resistance. The pressor effects of ET-1 were reduced by diltiazem, nitrendipine, verapamil or cromakalim and unchanged after BW 755c, desipramine, enalapril, indomethacin, methysergide, phentolamine or SK&F 100273. The sustained pressor response evoked by an i.v. infusion of ET-1 (0.25 nmol/kg/min/60 min) was also antagonized markedly by nitrendipine and cromakalim. In pithed rats with vasopressin-supported blood pressure, ET-1 produced a short-lasting hypotension which faded entirely after three successive injections of the peptide. Finally, ET-1 (0.4-0.8 nM) evoked greater contractile responses in rat aortic rings deprived of a functional endothelium than in intact preparations. However, in the latter preparation precontracted with norepinephrine, ET-1, in contrast to acetylcholine, failed to evoke vasorelaxation. In aortic rings, the sustained contractile effects of ET-1 (3.2 nM) were reduced moderately by nitrendipine (50 nM) and markedly by cromakalim (0.8 microM). In contrast, the latter compounds antagonized strongly the contractile response to KCl (25 mM). In conclusion, ET-1 appears to produce active vasorelaxation and vasoconstriction via stimulation of specific receptors on blood vessels. The tolerance to the hypotensive effect of ET-1 may indicate that either the receptor site for ET-1 becomes refractory or, alternatively, it is coupled to easily depletable endogenous hypotensive mediators. Finally, inasmuch as the vasoconstrictor effects of ET-1 can be easily counteracted by calcium antagonists under in vivo but not in vitro conditions, the membrane coupling mechanism for ET-1 may not be exactly the same in conductance or resistance vessels.     

经桡动脉途径肾动脉造影的临床效果评价

目的评价经桡动脉途径肾动脉造影的临床效果。方法入选2010年11月至2012年11月收治的100例冠心病合并高血压患者,按就诊时间随机分成桡动脉组(50例)与股动脉组(50例),分别经桡动脉、股动脉行肾动脉造影术,观察两组肾动脉造影手术时间、X线照射时间、手术成功情况及并发症等情况。结果桡动脉组、股动脉组肾动脉狭窄检出例数分别为9例(18.0%)、6例(12.0%),两组检出率比较无显著差异(P0.05);两组X线照射时间、手术操作时间对比差异无统计学意义(P0.05);桡动脉组手术成功率(80.0%)低于股动脉组(98.0%),桡动脉组并发症发生率(2.0%)亦低于股动脉组(10.0%),差异有显著性(P0.05)。结论经桡动脉途径行肾动脉造影的手术成功率略低于经股动脉肾动脉造影,但是可通过对导管的长度进行改进增加手术成功率。经桡动脉途径行肾动脉造影的并发症发生率略低于经股动脉肾动脉造影。所以,经桡动脉途径行肾动脉造影是安全可行的,临床应用价值较高。     

Embattled cannabis: pharmacological,medical, recreational,and adverse effects aspects

Cannabis sativa L. (Cannabaease), currently, is the most widely used illicit drug around the world. The psychoactive chemical of the plant is the (9)-tetrahydrocannabinol (THC). The federal government of the United States as well as other countries classified THC as Schedule I controlled substance. Concerning the use of cannabinoids as therapeutic agents exhibits beneficial therapeutic effects against nausea and vomiting in cancer and AIDS patients. Cannabis decreased the intensity of spasm and tremors in multiple sclerotic patients. On the other hand, the chronic use of Cannabis sativa may cause severe, unwanted, acute, and chronic side effects: cognition, coordination, learning defects, and impairment of memory among users, addiction, and possible suicidal attempts. Still, cannabis may trigger acute cardiovascular diseases including mortality, although there is some progress by introducing new agents that work like THC such as Sativex, Nabilone, and Conador. These agents await further extensive development to enhance efficacy and to decrease toxicity. In conclusion, the outcome of the medical use of cannabis is blurred with the presence of the recreational use. The question of whether it should be legalized still needs extensive discussion.     

Clinical effects of pharmacological variations in selective serotonin reuptake inhibitors: an overview

Although the selective serotonin reuptake inhibitor (SSRI) class of antidepressants shares a common primary pharmacology, namely the inhibition of serotonin reuptake, their secondary pharmacology is remarkably heterogeneous. Inhibition of serotonin reuptake and the consequent increase in serotonin availability are responsible for the relief of depressive symptoms and for some of the adverse effects of this class of drugs. Transsynaptic effects such as modulation of signalling cascades, gene expression processes and neuroplasticity are also important in the mechanism of action of antidepressants. However, this review shows that secondary properties of the SSRIs may contribute to the differences in efficacy and tolerability between members of the class. For example, fluvoxamine has affinity for sigma(1)-receptors -- a property likely to be responsible for its particular efficacy in delusional depression. By understanding the properties of SSRIs and employing careful selection of agents for individual patients, physicians are more able to tailor antidepressant treatments to their patients' particular circumstances.     

In-vitro evaluation of miokamycin: bactericidal activity against streptococci

Miokamycin is a diacetyl derivative of the macrolide antibiotic, midecamycin. In vitro, it has an unusual spectrum, inhibiting the growth of Gram-positive cocci and anaerobes, but few Haemophilus spp; enterobacteria are highly resistant. Most erythromycin-resistant Staphylococcus aureus were sensitive (MIC approximately 0.8 mg/l). Resistance to miokamycin in Staph. aureus and streptococci was difficult to select, unless the staphylococci were already resistant to erythromycin. Both miokamycin and erythromycin were bactericidal towards groups A,B,C and G streptococci. Clinical trials of the drug in pelvic, upper respiratory, skin and soft tissue and other staphylococcal infections may be worthwhile.     

Postantibiotic effects and bactericidal activities of clarithromycin-14-hydroxy-clarithromycin, versus those of amoxicillin-clavulanate, against anaerobes

The bactericidal activities and postantibiotic effects (PAE) of clarithromycin-14-hydroxy-clarithromycin and amoxicillin-clavulanate against Bacteroides fragilis and Peptostreptococcus anaerobius were determined. A concentration of twice the MIC resulted in bactericidal activity against four of four and three of four organisms at 24 h with clarithromycin-14-hydroxy-clarithromycin and amoxicillin-clavulanate, respectively. The PAE of clarithromycin-14-hydroxy-clarithromycin was 1.44 to 3.20 h, compared to the less than 1 h of amoxicillin-clavulanate. Clarithromycin-14-hydroxy-clarithromycin possesses good activity against susceptible anaerobes.     

Clinical evaluation of large volume subcutaneous injection tissue effects,pain, and acceptability in healthy adults

Determining feasibility and tolerability of large volume viscous subcutaneous injection may enable optimized, intuitive delivery system design. A translational early feasibility clinical study examined large volume subcutaneous injection viability, tolerability, acceptability, tissue effects and depot location for ~1, 8, and 20 cP injections at volumes up to 10 ml in the abdomen and 5 ml in the thigh in 32 healthy adult subjects. A commercial syringe pump system delivered 192 randomized, constant rate (20 µl/s) injections (6/subject) with in‐line injection pressure captured versus time. Deposition location was qualified via ultrasound. Tissue effects and pain tolerability were monitored through 2 hours post‐injection with corresponding Likert acceptability questionnaires administered through 72 hours. All injection conditions were feasible and well‐tolerated with ≥79.3% favorable subject responses for injection site appearance and sensation immediately post‐injection, increasing to ≥96.8% at 24 hours. Mean subject pain measured via 100 mm visual analog scale increased at needle insertion (6.9 mm, SD 10.8), peaked during injection (26.9 mm, SD 21.7) and diminished within 10 minutes post‐removal (1.9 mm, SD 4.2). Immediate injection site wheal (90.9%) and erythema (92.6%) formation was observed with progressive although incomplete resolution through 2 hours (44.6% and 11.4% remaining, respectively). Wheal resolution occurred more rapidly at lower viscosities. Most subjects (64.5%) had no preference between abdomen and thigh. Correlations between tissue effects, injection pressure and pain were weak (Pearson’s rho ± 0–0.4). The large volume injections tested, 1–20 cP viscosities up to 10 ml in the abdomen and 5 ml in the thigh, are feasible with good subject acceptability and rapid resolution of tissue effects and pain.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Traditional chronic disease intravenous therapy is transitioning to subcutaneous administration, creating viscous formulations delivered at volumes exceeding the traditional threshold of 1.5–3.0 ml. Understanding the local physiological impact and corresponding tolerability of large volume subcutaneous injection is key to optimized, intuitive delivery system design.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Early feasibility clinical to determine feasibility and tolerability of constant rate (20 µl/s), 1–20 cP, 5–10 ml subcutaneous placebo injections to the thigh and abdomen in healthy adults. Are injections and corresponding local tissue effects visible, acceptable, and quick to resolve?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Localized tissue effects (wheals and erythema) and pain are common but transient with broad, favorable acceptability for subcutaneous injections up to 10 ml and 20 cP. Pain peaks during injection, returning to pre‐injection levels within 30 minutes. Tissue effects are larger and slower to resolve for thigh and/ or higher volume and viscosity injections.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The tolerability and feasibility boundaries of large volume subcutaneous administration include and likely exceed the injection conditions tested.     

Antinociceptive and pharmacological effects of metanicotine, a selective nicotinic agonist.

Metanicotine [N-methyl-4-(3-pyridinyl)-3-butene-1-amine], a novel neuronal nicotinic agonist, was found to bind with high affinity (K(i) = 24 nM) to rat brain [(3)H]nicotine binding sites and it generalized to nicotine in a dose-dependent manner in the drug discrimination procedure. Metanicotine produced significant antinociceptive effects in mice and rats subjected to either acute thermal (tail-flick), mechanical (paw-pressure), chemical (para-phenylquinone), persistent (Formalin), and chronic (arthritis) pain stimuli. Metanicotine was about 5-fold less potent than nicotine in the tail-flick test after s.c administration, but slightly more potent after central administration. Its duration of action was longer than that of nicotine. Nicotinic antagonists, mecamylamine and dihydro-beta-erythroidine, blocked metanicotine-induced antinociception in the different pain models. However, the antinociceptive effect was not affected by pretreatment with either naloxone or by atropine, confirming that metanicotine exerts its antinociceptive effect via nicotinic rather than either opioid or muscarinic mechanisms. In contrast to nicotine, antinociceptive effects of metanicotine were observed at doses that had virtually no effect on spontaneous activity and body temperature in mice. These data indicate that metanicotine is a centrally acting neuronal nicotinic agonist with preferential antinociceptive effects in animals. Thus, metanicotine and related nicotinic agonists may have great potential for development as a new class of analgesics.     

Complementarity of in vitro and in vivo models for the evaluation of gastro‐protective effects of pharmacological substances

Gastric mucosa is frequently exposed to various gastric irritants, and there is a continuing requirement to develop new gastro‐protective agents. This study compares the effects of three such agents, sucralfate, rebamipide, and cimetidine in both in vivo and in vitro indomethacin‐induced gastric damage models. For the in vivo approach, rats were orally administered sucralfate, rebamipide, and cimetidine at 300 mg/kg before an acute dose of indomethacin (30 mg/kg). Gastric lesions were then macroscopically examined. For the in vitro approach, gastric mucosal cells were incubated with sucralfate (3 and 5 mg/mL), rebamipide (0.3 and 1 mm ), and cimetidine (10 and 50 μg/mL) before exposure to indomethacin (3.8 mm ). The release of lactate dehydrogenase (LDH) and mitochondrial function were then measured. Sucralfate, rebamipide, and cimetidine displayed gastro‐protective effects in vivo (decreased number of gastric ulcers: ?50% P < 0.05, ?22% NS, and ?69% P < 0.05, respectively, and reduced length of gastric lesions: ?62% P < 0.05, ?29% NS, and ?70% P < 0.001, respectively). Cell damage induced by indomethacin in vitro was inhibited by sucralfate (LDH release) and by rebamipide and cimetidine (mitochondrial function and LDH release). In contrast, sucralfate accentuated the indomethacin‐induced decrease in mitochondrial function. Although cultured gastric cells offer a promising tool for evaluating the cytotoxic or protective effects of test compounds, data from in vivo models are still needed to confirm in vitro data. Using both approaches provides more comprehensive insight into the effects of test compounds on the gastric mucosa.     

Nifekalant and disopyramide in a patient with short QT syndrome: evaluation of pharmacological effects and electrophysiological properties

We assessed several pharmacological effects on electrocardiogram parameters and effective refractory period (ERP) in a patient with a short QT syndrome (SQTS). Pharmacological challenge tests revealed that disopyramide and selective I_kr blocker, nifekalant normalized QT interval, and ERP of the atrial and ventricular myocardium. This study suggested that disopyramide and nifekalant should be feasible for the drug treatment of the SQTS. Moreover, QT interval was paradoxically prolonged at higher heart rates induced with isoproterenol infusion or an exercise test, although the mechanism of this QT prolongation remains to be investigated.